title: Heme oxygenase-1 exerts a protective role in ovalbumin-induced neutrophilic airway inflammation by inhibiting Th17 cell-mediated immune response.
abstract: Allergic asthma is conventionally considered as a Th2 immune response characterized by eosinophilic inflammation. Recent investigations revealed that Th17 cells play an important role in the pathogenesis of non-eosinophilic asthma (NEA), resulting in steroid-resistant neutrophilic airway inflammation. Heme oxygenase-1 (HO-1) has anti-inflammation, anti-oxidation, and anti-apoptosis functions. However, its role in NEA is still unclear. Here, we explore the role of HO-1 in a mouse model of NEA. HO-1 inducer hemin or HO-1 inhibitor tin protoporphyrin IX was injected intraperitoneally into ovalbumin-challenged DO11.10 mice. Small interfering RNA (siRNA) was delivered into mice to knock down HO-1 expression. The results show that induction of HO-1 by hemin attenuated airway inflammation and decreased neutrophil infiltration in bronchial alveolar lavage fluid and was accompanied by a lower proportion of Th17 cells in mediastinal lymph nodes and spleen. More importantly, induction of HO-1 down-regulated Th17-related transcription factor retinoic acid-related orphan receptor γt (RORγt) expression and decreased IL-17A levels, all of which correlated with a decrease in phosphorylated STAT3 (p-STAT3) level and inhibition of Th17 cell differentiation. Consistently, the above events could be reversed by tin protoporphyrin IX. Also, HO-1 siRNA transfection abolished the effect of hemin induced HO-1 in vivo. Meanwhile, the hemin treatment promoted the level of Foxp3 expression and enhanced the proportion of regulatory T cells (Tregs). Collectively, our findings indicate that HO-1 exhibits anti-inflammatory activity in the mouse model of NEA via inhibition of the p-STAT3-RORγt pathway, regulating kinetics of RORγt and Foxp3 expression, thus providing a possible novel therapeutic target in asthmatic patients.
authors.affiliation: From the Department of Pediatrics, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liya
authors.initials: L
authors.lastname: Zhang
authors.forename: Jinhong
authors.initials: J
authors.lastname: Wu
authors.forename: Caixia
authors.initials: C
authors.lastname: Di
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006427:Hemin / Q000008:administration & dosage; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008665:Metalloporphyrins / Q000008:administration & dosage; D051379:Mice; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011524:Protoporphyrins / Q000008:administration & dosage; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D008665:Metalloporphyrins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D006427:Hemin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1
keywords: Asthma; Heme Oxygenase; Immunology; Inflammation; T Cell; Th17; Treg